Welcome to the Plotkin Research Group!
Plotkin Group members, Left to right: Pranav Garg, Kathryn Lande, Aina Adekunle, Kyra Boulding, Dr. Steven Plotkin, Dr. Luke McAlary, Shawn Hsueh, Lana Kashino, Tiam Heydari ( Not shown: Mine Sher)
Come meet the members of our group, review our current research, and find out how you can join, We are currently looking for experimental researchers in either the developmental biology or protein misfolding projects below.
In Silico Mechanical Manipulation of Misfolding-Prone Proteins
A protein is a linear chain of amino acids made up of about a couple thousand atoms, all of which are fluctuating around furiously in our bodies because our cells are full of thermal energy. However, the atoms in a protein are still being held together amidst this chaotic motion by internal forces inside the protein. We found that a protein is in fact made up a composite of soft and rigid regions, and that where these regions are can be discovered by taking the protein in the absence of any thermal energy, and "pinging" it like a tuning fork to see how it vibrates. The vibrations disperse all over the protein in a complicated way, but the rigid parts vibrate quickly when pinged, and the soft parts vibrate slowly when pinged.
This study was done in the virtual environment of a computer simulation, allowing us to go further in the analysis of how the protein unravels. We use the strength of computer simulation to perform analysis similar to what experimental spectroscopists do in much larger, condensed matter systems. It is possi ble in principle to experimentally get at the quantities we have been measuring, but several experiments would be needed with several protein labels; these experiments haven't been done yet.
If a protein is grabbed by the ends and gradually pulled apart, we found that the slowly vibrating soft regions tend to be the first to unfold. As the protein unfolds however, the soft and hard regions meander about the protein in a way that is difficult to predict, but the soft regions may be repeatedly calculated during the process of unfolding, to give new predictions as the next part of the protein begins to unfold.
This study provides many insights into the unfolding events of a protein; superoxide dismutase (SOD1) was used in the study because there is experimental evidence that partially unfolded conformations of this protein could be harmful to a neuron cell. In addition, this study connects two disparate areas of inquiry: the so-called "force-spectroscopy" of unfolding proteins at play when pulling them apart, and the breaking or fracture events that occur in glassy systems, which can also be predicted from slow and fast vibrations. In this sense, a protein being pulled on is like a composite "nano-glass", and how soft or hard a part of the protein is at that moment can tell us if it is the next to break.
Habibi M, Plotkin SS, Rottler J, "Soft Vibrational Modes Predict Breaking Events during Force-Induced Protein Unfolding", Biophysical Journal, Volume 114, Issue 3, Pages 562-569. (2018)
Habibi M, Rottler J, and Plotkin SS "The Unfolding Mechanism of Monomeric Mutant SOD1 by Simulated Force Spectroscopy", Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1865, Issue 11, Part B. (2017)
Habibi M, Rottler J, and Plotkin SS "As Simple as Possible but not Simpler: Exploring the Fidelity of Coarse-Grained Protein Models for Simulated Force Spectroscopy", PLoS Comput Biol 12(11): e1005211 (2016)
Molecular-Genetic Origins of Multicellularity
The embryologic question of how a multicellular organism can arise from a single cell is intimately linked with the equally fundamental evolutionary question of how complex multicellular organisms arose from single-celled ancestors. The origin of multicellularity is a pivotal transition to complex life, as it was a necessary precursor to higher life forms containing complex organs including brains. However, it remains enigmatic as most of the molecular, genetic, and evolutionary mechanisms involved in the transition are only beginning to be unraveled.
Multicellularity emerges when cells cooperatively differentiate and organize spatially into an integrated organism in a process that is genetically encoded for successive generations to reliably reproduce from a single progenitor cell. Depending on the degree to which cellular aggregation, sustained cell-to-cell inter-connection, communication, and cooperation are integrated, the transition to multicellularity has occurred anywhere from about a dozen to about 40 independent times across the tree of life during evolutionary history. The repeated instances of this transition across distinct environments and various epochs, and on different phylogenetic backgrounds, suggests that multicellularity is a phenomenon that arose, and can ?arise, as a generic physicochemical response to various environmental pressures. In this sense then it is a natural consequence of evolution, and a universal aspect of life.
This is a new project that has become one of the primary focuses of our lab. We will investigate the function and evolution of genetic regulatory networks (GRNs) involved in the process of cell differentiation; we are currently using CRISPR/Cas9 genetic manipulation methods in model and non-model organisms to address this question.